This invention relates to 1H-Pyrrolo[3,2-b]pyridine-3-carboxylic acid amides that bind to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in the treatment of central nervous system (CNS) diseases.
The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, xcex3-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed throughout the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization. In addition to being the site of neurotransmitter action, a number of drugs including the anxiolytic and sedating benzodiazepines bind to this receptor. The GABAA receptor comprises a chloride channel that generally, but not invariably, opens in response to GABA, allowing chloride to enter the cell. This, in turn, effects a slowing of neuronal activity through hyperpolarization of the cell membrane potential.
GABAA receptors are composed of five protein subunits. A number of cDNAs for these GABAA receptor subunits have been cloned and their primary structures determined. While these subunits share a basic motif of 4 membrane-spanning helices, there is sufficient sequence diversity to classify them into several groups. To date at least 6xcex1, 3xcex2, 3xcex3, 1xcex5, 1xcex4 and 2xcfx81 subunits have been identified. Native GABAA receptors are typically composed of 2xcex1, 2xcex2, and 1xcex3. Various lines of evidence (such as message distribution, genome localization and biochemical study results) suggest that the major naturally occurring receptor combinations are xcex11xcex22xcex32, xcex12xcex22xcex32, xcex13xcex23xcex32, and xcex15xcex23xcex32 (Mohler et al. Neuroch. Res. 1995; 20(5):631-36).
The GABAA receptor binding sites for GABA (2 per receptor complex) are formed by amino acids from the xcex1 and xcex2 subunits. Amino acids from the xcex1 and xcex3 subunits together form one benzodiazepine site per receptor. Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABAA receptor. In addition to the benzodiazepine site (sometimes referred to as the benzodiazepine or BDZ receptor), the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and a barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for other classes of drugs that bind to the receptor or for GABA (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York).
In a classic allosteric mechanism, the binding of a drug to the benzodiazepine site increases the affinity of the GABA receptor for GABA. Benzodiazepines and related drugs that enhance the ability of GABA to open GABAA receptor channels are known as agonists or partial agonists depending on the level of GABA enhancement. Other classes of drugs, such as xcex2-carboline derivatives, that occupy the same site and negatively modulate the action of GABA are called inverse agonists. A third class of compounds exists which occupy the same site as both the agonists and inverse agonists and yet have little or no effect on GABA activity. These compounds will, however, block the action of agonists or inverse agonists and are thus referred to as GABAA receptor antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early, and the distribution of activities at different subtype receptors has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have enjoyed long pharmaceutical use as anxiolytics, these compounds are known to exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABAA selective ligands may also act to potentiate the effects of certain other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABAA selective ligands than when used alone.
This invention provides 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid amides that bind preferably with high affinity and high selectivity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Compounds of the invention preferably bind with high selectivity and/or high affinity to GABAA receptors and thereby act as agonists, antagonists or inverse agonists of such receptors. As such, they are useful in the treatment of various CNS disorders.
The invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I.
The invention further provides methods of treating patients suffering from certain CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering from certain CNS disorders with an effective amount of a compound of the invention is encompassed by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention in conjunction with the administration of another CNS active compound.
Additionally this invention relates to the use of compounds of Formula I as probes for the localization of GABAA receptors in tissue sections.
In a first aspect the invention provides compounds and pharmaceutically acceptable salts of Formula I 
The invention includes 3 classes of compounds of Formula I, these classes of compounds will be referred to as Class 1, Class 2, and Class 3.
The substitutents R1, R2, and R3 carry the same definitions for all three classes of compounds 1, 2, and 3. Thus, for each of classes 1, 2, and 3, R1, R2, and R3 independently represent:
A) hydrogen, halogen, halo(C1-C6)alkyl, hydroxy, cyano, amino, alkyl, alkoxy, mono(C1-C6)alkylamino, di-(C1-C6)alkylamino, mono(C1-C6)alkylamino(C1-C6)alkyl, di-(C1-C6)alkylamino(C1-C6)alkyl, xe2x80x94C(xe2x95x90O)NR10R11, xe2x80x94C(xe2x95x90O)OR10, and xe2x80x94OC(xe2x95x90O)R10, xe2x80x94C(xe2x95x90O)R10, where R10 or R11 are independently hydrogen, C1-C6 alkyl, phenyl, phenyl(C1-C6)alkyl, pyridyl, or pyridyl(C1-C6)alkyl; or
B) haloalkoxy, alkenyl, alkynyl, hydroxyalkyl, xe2x80x94DR20, xe2x80x94Exe2x80x94R35, xe2x80x94C1-C4alkyl-DR20, xe2x80x94C1-C4alkyl-Oxe2x80x94R20, xe2x80x94Exe2x80x94R20xe2x80x94Gxe2x80x94R30, xe2x80x94Exe2x80x94L, xe2x80x94Exe2x80x94R20xe2x80x94L, J, xe2x80x94C(xe2x95x90O)xe2x80x94L, or xe2x80x94C1-C4alkyl-J;
where
D represents xe2x80x94S(O)nxe2x80x94, xe2x80x94S(O)nNHxe2x80x94, xe2x80x94S(O)nNH2, xe2x80x94S(O)nNR30xe2x80x94, xe2x80x94NHC(xe2x95x90O)xe2x80x94, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94NR30C(xe2x95x90O)xe2x80x94, xe2x80x94NR30C(xe2x95x90O)H, xe2x80x94NHS(O)nxe2x80x94, or xe2x80x94NR30S(O)nxe2x80x94;
E and G are independently NH, Nxe2x80x94C1-C6alkyl, S, and O;
each R20 and R30 is independently a (C1-C8)straight, (C1-C8)branched, (C3-C8)cyclic alkyl or (C3-C8)cycloalkyl(C1-C6)alkyl group, where each alkyl and cycloalkyl group contains zero or one or more double or triple bonds and where each carbon atom in the R20 and R30 groups is optionally substituted with one or more subsitutents independently selected from group C), where group C) consists of oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), xe2x80x94NHC(xe2x95x90O)(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)C(xe2x95x90O)(C1-C6alkyl), xe2x80x94NHS(O)n(C1-C6alkyl), xe2x80x94S(O)n(C1-C6alkyl), xe2x80x94S(O)nNH(C1-C6alkyl), xe2x80x94S(O)nN(C1-C6alkyl)(C1-C6alkyl), or L, where n is 0, 1, or 2;
each R35 is independently a (C1-C8)straight, (C1-C8)branched, (C3-C8)cyclic alkyl or (C3-C8)cycloalkyl(C1-C6)alkyl group, where each alkyl and cycloalkyl group contains zero or one or more double or triple bonds and where each carbon atom in R35 is substituted with one or more substituents independently selected from group C);
J and L are independently selected at each occurrence from saturated, partially unsaturated, and aromatic rings having from 4 to 7 ring atoms, where 0, 1, or 2 of the ring atoms are oxygen or nitrogen, and the remaining ring atoms are carbon atoms, where the rings are unsubstituted or substituted with one or more substituents which are independently
i) halogen, oxo, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, or mono- or di-(C1-C6)alkylamino; or
ii) phenyl, pyridyl, pyrimidyl, or pyrazinyl, each of which is unsubstituted or substituted with from 1 to 3 of halogen, hydroxy, amino, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy, and mono- or di-(C1-C4)alkylamino; or
R4 is hydrogen, halogen, or hydroxyl.
For compounds of Class 1, at least 1 of R1, R2, and R3 is selected from B) and J is not phenyl or pyridyl.
The variable xe2x80x9cArxe2x80x9d is defined differently for each of Classes 1, 2, and 3.
For compounds and salts of Class 1:
Ar represents an aryl, arylalkyl, heteroarylalkyl or heteroaryl group, each aryl or heteroaryl having 1 or 2 aromatic rings and 4 to 7 ring atoms in each aromatic ring, where 0, 1, or 2 of the ring atoms chosen are oxygen, nitrogen, or sulfur and the remaining ring atoms are carbon atoms and where each ring is optionally substituted with 1 or more of R40, where
R40 is independently selected at each occurrence from hydroxy, halogen, cyano, nitro, amino, XR50, C1-C4alkyl-XR50, and Y;
X is independently selected at each occurrence from the group consisting of a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CHR60xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, xe2x80x94OC(xe2x95x90O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR60xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, xe2x80x94C(xe2x95x90O)NR60xe2x80x94, xe2x80x94S(O)nNHxe2x80x94, xe2x80x94S(O)nNR60xe2x80x94, xe2x80x94NHC(xe2x95x90O)xe2x80x94, xe2x80x94NR60C(xe2x95x90O)xe2x80x94, xe2x80x94NHS(O)nxe2x80x94, and xe2x80x94NR60S(O)nxe2x80x94; where n is 0, 1, or 2;
R50 and R60 are independently selected at each occurrence from hydrogen, C1-C8 alkyl, C3-C8cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl, where each alkyl and cycloalkyl contains zero or one or more double or triple bonds, and where each carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl is optionally independently substituted with one or more of oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), xe2x80x94NHC(xe2x95x90O)(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)C(xe2x95x90O)(C1-C6alkyl), xe2x80x94NHS(O)n(C1-C6alkyl), xe2x80x94S(O)n(C1-C6alkyl), xe2x80x94S(O)nNH(C1-C6alkyl), xe2x80x94S(O)nN(C1-C6alkyl)(C1-C6alkyl), and Z, where n is 0, 1, or 2; and
Y and Z are independently selected at each occurrence from saturated, partially unsaturated, and aromatic rings having from 4 to 7 ring atoms in each aromatic ring, where 0, 1, or 2 ring atoms are oxygen or nitrogen and the remaining ring atoms are carbon, and wherein Y and Z are independently unsubstituted or substituted with one or more of halogen, oxo, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, or mono- or di-(C1-C6)alkylamino.
For compounds and salts of Class 2:
Ar represents heteroaryl or heteroaryl(C1-C6)alkyl, where the heteroaryl is selected from quinolinyl, benzothienyl, indolyl, pryidazinyl, pyazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thienyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl, dihydro-benzodioxinyl, furanyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanonyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide, wherein Ar is optionally substituted by 1 or more of R40.
Each R40 for the compounds of Class 2 is independently hydroxy, halogen, cyano, nitro, amino, XR50, C1-C4alkyl-XR50, or Y;
where each X is independently a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CHR60xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, xe2x80x94OC(xe2x95x90O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR60xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, xe2x80x94C(xe2x95x90O)NR60xe2x80x94, xe2x80x94S(O)nNHxe2x80x94, xe2x80x94S(O)nNR60xe2x80x94, xe2x80x94NHC(xe2x95x90O)xe2x80x94, xe2x80x94NR60C(xe2x95x90O)xe2x80x94, xe2x80x94NHS(O)nxe2x80x94, and xe2x80x94NR60S(O)nxe2x80x94, where n is 0, 1, or 2;
R50 and R60 are independently selected at each occurrence from hydrogen, C1-C8 alkyl, C3-C8cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl, where each alkyl and cycloalkyl contains zero or one or more double or triple bonds, and where each carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl is optionally independently substituted with one or more of oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), xe2x80x94NHC(xe2x95x90O)(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)C(xe2x95x90O)(C1-C6alkyl), xe2x80x94NHS(O)n(C1-C6alkyl), xe2x80x94S(O)n(C1-C6alkyl), xe2x80x94S(O)nNH(C1-C6alkyl), xe2x80x94S(O)nN(C1-C6alkyl)(C1-C6alkyl), and Z, where n is 0, 1, or 2; and
Y and Z are independently selected at each occurrence from saturated, partially unsaturated, and aromatic rings having from 4 to 7 ring atoms in each aromatic ring, where 0, 1, or 2 ring atoms are oxygen or nitrogen and the remaining ring atoms are carbon, and wherein Y and Z are independently unsubstituted or substituted with one or more of halogen, oxo, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, or mono- or di-(C1-C6)alkylamino.
For compounds and salts of Class 3:
Ar represents phenyl, pyridyl, or pyrimidinyl each of which is optionally substituted with 1 or more of R40; where each R40 is independently hydroxy, halogen, cyano, nitro, amino, C1-C6alkyl, C1-C6alkoxy, C1-C6alkanoyl, C3-C7cycloalkyl, C3-C7cycloalkyl(C1-C4)alkyl, C3-C7cycloalkyl-Oxe2x80x94, C3-C7cycloalkyl(C1-C4)alkoxy-, C2-C6alkenyl, C1-C6alkylthio-, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy.
In addition, Ar in the compounds and salts of Class 3 must is substituted by at least one of xe2x80x94Exe2x80x94R50xe2x80x94Gxe2x80x94R60, xe2x80x94Exe2x80x94R50xe2x80x94Gxe2x80x94Y, C1-C4alkyl-XR50, xe2x80x94NHxe2x80x94R60xe2x80x94Y, xe2x80x94(NR50)R60xe2x80x94Y, or Y;
where X is independently selected at each occurrence from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, xe2x80x94OC(xe2x95x90O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR60xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, xe2x80x94C(xe2x95x90O)NR60xe2x80x94, xe2x80x94S(O)nNHxe2x80x94, xe2x80x94S(O)nNR60xe2x80x94, xe2x80x94NHC(xe2x95x90O)xe2x80x94, xe2x80x94NR60C(xe2x95x90O)xe2x80x94, xe2x80x94NHS(O)nxe2x80x94, and xe2x80x94NR60S(O)nxe2x80x94, where n is 0, 1, or 2;
R50 and R60 are independently selected at each occurrence from hydrogen, C1-C8 alkyl, C3-C8cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl, where each alkyl and cycloalkyl contains zero or one or more double or triple bonds, and where each carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl is optionally independently substituted with one or more of oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), xe2x80x94NHC(xe2x95x90O)(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)C(xe2x95x90O)(C1-C6alkyl), xe2x80x94NHS(O)n(C1-C6alkyl), xe2x80x94S(O)n(C1-C6alkyl), xe2x80x94S(O)nNH(C1-C6alkyl), xe2x80x94S(O)nN(C1-C6alkyl)(C1-C6alkyl), and Z, where n is 0, 1, or 2; and
Y and Z are independently selected at each occurrence from saturated, partially unsaturated, and aromatic rings having from 4 to 7 ring atoms in each aromatic ring, where 0, 1, or 2 ring atoms are oxygen or nitrogen and the remaining ring atoms are carbon, and wherein Y and Z are independently unsubstituted or substituted with one or more of halogen, oxo, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, or mono- or di-(C1-C6)alkylamino.
Specific embodiments of the invention include compounds and pharmaceutically acceptable salts, Classes 1, 2, and 3, in which R4 is hydrogen.
Additionally, the invention is directed to Class 1 compounds and salts of Formula I wherein Ar represents an aryl, arylalkyl, heteroaryl, or heteroarylalkyl group, the aryl or heteroaryl of which is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl [1,3,4]thiadiazolyl, triazolyl, indolyl, quionolinyl, isoquinolinyl benzodioxolyl, benzofuranyl, benzimiazolyl, benzoisoxolyl, and dihydro-benzodioxinyl, and is optionally substituted by one or more of R40, and R40 is as defined above. Such compounds are hereinafter referred to as compounds of Class 1A.
The invention also includes compounds and pharmaceutically acceptable salts of Formula I, Class 1, wherein R1 is selected from B).
In this aspect, R2 and R3 are independently selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, and mono- or di-(C1-C6)alkylamino; more preferably R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, xe2x80x94OCF3, hydroxy, cyano, C1-C2alkyl, C1-C2alkoxy, and mono- or di-(C1-C2)alkylamino, or R2 and R3 may be independently selected from hydrogen, halogen, methyl and ethyl.
In this aspect, R4 is preferably hydrogen; and Ar is as defined for compounds of Class 1A.
Further included in the invention are compounds and pharmaceutically acceptable salts of Formula I, Class 1A. Compounds and salts of Formula I, Class 1A are those where:
R1 is selected from B);
R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl;
R4 is preferably hydrogen; and
R40 is independently selected at each occurrence from C1-C6alkyl, C1-C6alkoxy; halogen, mono or di-(C1-C6)alkylamino, mono or di-(C1-C6)alkylamino(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, and (C1-C6)alkoxy(C1-C6)alkoxy.
The invention is directed to another embodiment that includes compounds and pharmaceutically acceptable salts of Formula I, Class 1A, in which:
R1 is selected from B); and B) in this embodiment is xe2x80x94Exe2x80x94R35, xe2x80x94C1-C4alkyl-Oxe2x80x94R20, xe2x80x94Exe2x80x94R20xe2x80x94Gxe2x80x94R30, xe2x80x94Exe2x80x94L, xe2x80x94Exe2x80x94R20xe2x80x94L, J, or xe2x80x94C1-C4alkyl-J; and
E and G in this embodiment are independently NH, Nxe2x80x94C1-C6alkyl, or O.
In this embodiment, R20, R30, and R35 of the invention are independently selected at each occurrence from: straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, wherein in R20 and R35 each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from group C) and in R35 at least one of which 1 to 8 carbon atoms is further substituted by one or more substituent(s) independently selected from group C) wherein group C) consists of: oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), xe2x80x94NHC(xe2x95x90O)(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)C(xe2x95x90O)(C1-C6alkyl), xe2x80x94NHS(O)n(C1-C6alkyl), xe2x80x94S(O)n(C1-C6alkyl), xe2x80x94S(O)nNH(C1-C6alkyl), xe2x80x94S(O)nN(C1-C6alkyl)(C1-C6alkyl), and L.
J and L are independently selected at each occurrence from: saturated heterocyclic rings having from 4 to 7 ring atoms, wherein 1 or 2 ring atoms are nitrogen, with remaining ring atoms being carbon, which rings are unsubstituted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, and mono- or di-(C1-C6)alkylamino; with the proviso that J is not unsubstituted or substituted phenyl or unsubstituted or substituted pyridyl.
R2 and R3 in this embodiment are independently selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, and mono- or di-(C1-C6)alkylamino; more preferably R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, xe2x80x94OCF3, hydroxy, cyano, C1-C2alkyl, C1-C2alkoxy, and mono- or di-(C1-C2)alkylamino, or R2 and R3 may be independently selected from hydrogen, halogen, methyl and ethyl;
R4 is preferably hydrogen; and
R40 is independently selected at each occurrence from C1-C6alkyl, C1-C6alkoxy; halogen, mono or di-(C1-C6)alkylamino, mono or di-(C1-C6)alkylamino(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, and (C1-C6)alkoxy(C1-C6)alkoxy.
The invention further includes compounds and pharmaceutically acceptable salts of Formula I, Class 1 wherein Ar carries the definition set forth for compounds and salts of Class 1A and
R40 is independently selected at each occurrence from hydroxy, halogen, cyano, amino, XR50, xe2x80x94(C1-C4)alkyl-XR50, and Y;
X is independently selected at each occurrence from the group consisting of a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CHR60xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR60xe2x80x94, where n is 0, 1, or 2;
R50 and R60 are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), xe2x80x94NHC(xe2x95x90O)(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)C(xe2x95x90O)(C1-C6alkyl), xe2x80x94NHS(O)n(C1-C6alkyl), xe2x80x94S(O)n(C1-C6alkyl), xe2x80x94S(O)nNH(C1-C6alkyl), xe2x80x94S(O)nN(C1-C6alkyl)(C1-C6alkyl), and Z, where n is 0, 1, or 2; and
Y and Z are independently selected at each occurrence from: saturated, partially unsaturated, or aromatic rings having from 4 to 7 ring atoms, 0, 1, or 2 ring atoms chosen from oxygen and nitrogen, with remaining ring atoms being carbon, wherein Y and Z are unsubstituted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, and mono- or di-(C1-C6)alkylamino. Such compounds will be referred to as compounds of Class 1B.
Additional embodiments of the invention are directed to compounds and pharmaceutically acceptable salts of Class 1B in which
R1 is selected from B);
R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl; and
R4 is preferably hydrogen.
In another embodiment, the invention is directed to compounds and pharmaceutically acceptably salts of Formula I, Class 2. In this embodiment, Ar represents an aryl, arylalkyl, heteroaryl, or heteroarylalkyl group, the aryl or heteroaryl of which is selected from piperazinyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl [1,3,4]thiadiazolyl, triazolyl, indolyl, quionolinyl, isoquinolinyl benzodioxolyl, benzofuranyl, benzimiazolyl, benzoisoxolyl, and dihydro-benzodioxinyl, and is optionally substituted by one or more of R40, wherein R40 carries the definition set forth above for compounds of Class 2. Such compounds will be referred to as compounds of Class 2A.
The invention is also directed to compounds and pharmaceutically acceptable salts of Formula I, Class 2A wherein
R1 is selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, mono- or di-(C1-C6)alkylamino and B).
R2 and R3 in this embodiment are independently selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, and mono- or di-(C1-C6)alkylamino, or more preferably R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, xe2x80x94OCF3, hydroxy, cyano, C1-C2alkyl, C1-C2alkoxy, and mono- or di-(C1-C2)alkylamino, or R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl.
In the compounds of Formula I, Class 2A, R4 is preferably hydrogen.
Another embodiment of the invention is directed to compounds and pharmaceutically acceptable salts of Formula I, Class 2A in which
R1 is selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, mono- or di-(C1-C6)alkylamino and B), and B) is xe2x80x94Exe2x80x94R35, xe2x80x94C1-C4alkyl-Oxe2x80x94R20, xe2x80x94Exe2x80x94R20xe2x80x94Gxe2x80x94R30, xe2x80x94Exe2x80x94L, xe2x80x94Exe2x80x94R20xe2x80x94L, J, or xe2x80x94C1-C4alkyl-J.
E and G are independently NH, Nxe2x80x94C1-C6alkyl, or O;
R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl; and
R4 is hydrogen.
Another embodiment of the invention is directed to compounds and pharmaceutically acceptable salts of Formula I, Class 2A in which Ar, which is defined as for compounds of Class 2A, is optionally substituted by one or more of R40. 
R40 in this embodiment is independently selected at each occurrence from C1-C6alkyl, C1-C6alkoxy; halogen, mono or di-(C1-C6)alkylamino, mono or di-(C1-C6)alkylamino(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, and (C1-C6)alkoxy(C1-C6)alkoxy.
In this embodiment, R1 in this embodiment is selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, mono- or di-(C1-C6)alkylamino and B).
R2 and R3 in this embodiment are independently selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, and mono- or di-(C1-C6)alkylamino, or more preferably R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, xe2x80x94OCF3, hydroxy, cyano, C1-C2alkyl, C1-C2alkoxy, and mono- or di-(C1-C2)alkylamino, or R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl.
R4 in this embodiment is hydrogen.
Another embodiment of the invention includes compounds and pharmaceutically acceptable salts of Formula I, Class 2A, in which Ar, which is defined as for compounds of Class 2A, is optionally substituted by one or more of R40. R40 for this embodiment is independently selected at each occurrence from C1-C6alkyl, C1-C6alkoxy; halogen, mono or di-(C1-C6)alkylamino, mono or di-(C1-C6)alkylamino(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, and (C1-C6)alkoxy(C1-C6)alkoxy.
R1 is selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, mono- or di-(C1-C6)alkylamino and B).
B) in this embodiment is xe2x80x94R35, xe2x80x94C1-C4alkyl-Oxe2x80x94R20, xe2x80x94Exe2x80x94R20xe2x80x94Gxe2x80x94R30, xe2x80x94Exe2x80x94L, xe2x80x94Exe2x80x94R20xe2x80x94L, J, or xe2x80x94C1-C4alkyl-J, where E and G are independently NH, Nxe2x80x94C1-C6alkyl, or O.
R20, R30, and R35 in this embodiment are independently selected at each occurrence from straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, wherein in R20 and R35 each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from group C) and in R35 at least one of which 1 to 8 carbon atoms is further substituted by one or more substituent(s) independently selected from group C) wherein group C) consists of: oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), xe2x80x94NHC(xe2x95x90O)(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)C(xe2x95x90O)(C1-C6alkyl), xe2x80x94NHS(O)n(C1-C6alkyl ), xe2x80x94S(O)n(C1--C6alkyl), xe2x80x94S(O)nNH(C1-C6alkyl), xe2x80x94S(O)nN(C1-C6alkyl)(C1-C6alkyl), and L.
J and L in this embodiment are independently selected at each occurrence from: saturated heterocyclic rings having from 4 to 7 ring atoms, wherein 1 or 2 ring atoms are nitrogen, with remaining ring atoms being carbon, which rings are unsubstituted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, and mono- or di-(C1-C6)alkylamino; with the proviso that J is not phenyl or pyridyl;
R2 and R3 in this embodiment are independently selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, and mono- or di-(C1-C6)alkylamino, or more preferably R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, xe2x80x94OCF3, hydroxy, cyano, C1-C2alkyl, C1-C2alkoxy, and mono- or di-(C1-C2)alkylamino, or R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl.
R4 in this embodiment is preferably hydrogen.
The invention also includes compounds and pharmaceutically acceptable salts of Formula I, where Ar is as defined for compounds of Class 2A.
R40 in this embodiment is independently selected at each occurrence from hydroxy, halogen, cyano, amino, XR50, xe2x80x94(C1-C4)alkyl-XR50, and Y.
X in this embodiment is independently selected at each occurrence from the group consisting of a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CHR60xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR60xe2x80x94, where n is 0, 1, or 2.
R50 and R60 in this embodiment are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), xe2x80x94NHC(xe2x95x90O)(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)C(xe2x95x90O)(C1-C6alkyl), xe2x80x94NHS(O)n(C1-C6alkyl), xe2x80x94S(O)n(C1-C6alkyl), xe2x80x94S(O)nNH(C1-C6alkyl), xe2x80x94S(O)nN(C1-C6alkyl)(C1-C6alkyl), and Z, where n is 0, 1, or 2.
Y and Z in this embodiment are independently selected at each occurrence from: saturated, partially unsaturated, or aromatic rings having from 4 to 7 ring atoms, 0, 1, or 2 ring atoms chosen from oxygen and nitrogen, with remaining ring atoms being carbon, wherein Y and Z are unsubstituted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, and mono- or di-(C1-C6)alkylamino. Such compounds will be referred to as compounds of Class 2B.
Other compounds and salts of Formula I, Class 2B included in the invention are those wherein R1 is selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, mono- or di-(C1-C6)alkylamino and B);
R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl; and
R4 is hydrogen.
The invention is directed to compounds and pharmaceutically acceptable salts of Formula I, Class 3, in which R1 is selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, and mono- or di-(C1-C6)alkylamino and B).
In this embodiment, R2 and R3 are independently selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, and mono- or di-(C1-C6)alkylamino or preferably R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, xe2x80x94OCF3, hydroxy, cyano, C1-C2alkyl, C1-C2alkoxy, and mono- or di-(C1-C2)alkylamino; and
R4 is preferably hydrogen.
Other compounds of Formula I, Class 3 are those wherein Ar, which is phenyl, pyridyl, or pyrimidinyl, each of which is optionally substituted by 1 or more of R40, where
R40 is preferably selected independently at each occurrence from hydroxy, halogen, cyano, amino, C1-C6alkyl, C1-C6alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy.
Ar in this embodiment is also substituted by at least one of xe2x80x94Exe2x80x94R50xe2x80x94Gxe2x80x94R60, xe2x80x94Exe2x80x94R50xe2x80x94Gxe2x80x94Y, C1-C4alkyl-XR50, xe2x80x94NHxe2x80x94R60xe2x80x94Y, xe2x80x94(NR50)R60xe2x80x94Y, and Y, where
X is independently selected at each occurrence from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, xe2x80x94OC(xe2x95x90O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR60xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, xe2x80x94C(xe2x95x90O)NR60xe2x80x94, xe2x80x94NHC(xe2x95x90O)xe2x80x94, andxe2x80x94NR60C(xe2x95x90O);
R50 and R60 are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), xe2x80x94NHC(xe2x95x90O)(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)C(xe2x95x90O)(C1-C6alkyl), and Z.
R2 and R3 in preferred embodiments of the invention are independently selected from hydrogen, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, cyano, amino, C1-C6alkyl, C1-C6alkoxy, and mono- or di-(C1-C6)alkylamino or preferably R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, xe2x80x94OCF3, hydroxy, cyano, C1-C2alkyl, C1-C2alkoxy, and mono- or di-(C1-C2)alkylamino, or from hydrogen, halogen, methyl and ethyl.
In this embodiment, R4 is preferably hydrogen.
Other preferred compounds of Formula I include those where
R1 is amino(C1-C6)alkoxy, mono(C1-C3)alkylamino(C1-C6)alkoxy, di(C1-C3)alkylamino(C1-C6)alkoxy, pyridyl(C1-C6)alkoxy, hydroxy(C1-C6)alkoxy, (C1-C4)alkoxy(C1-C6)alkoxy, piperazinyl(C1-C6)alkoxy wherein the piperazinyl group is optionally substituted with (C1-C6)alkyl, morpholinyl(C1-C6)alkoxy, or thiomorpholinyl(C1-C6)alkoxy;
R2 and R3 are independently selected from H, (C1-C6)alkyl, halogen or (C1-C6)alkoxy.
Within this preferred aspect, other preferred compounds of Formula I are those where both R2 and R3 are both hydrogen.
More preferred compounds of Formula I include those where
R1 is amino(C1-C4)alkoxy, mono(C1-C4)alkylamino(C1-C4)alkoxy, di(C1-C4)alkylamino(C1-C4)alkoxy, pyridyl(C1-C4)alkoxy, hydroxy(C1-C4)alkoxy, piperazinyl(C1-C4)alkoxy wherein the piperazinyl group is optionally substituted with (C1-C4)alkyl, or morpholinyl(C1-C6)alkoxy.
Within this preferred aspect, other preferred compounds of Formula I are those where both R2 and R3 are both hydrogen.
Still more preferred compounds of Formula I include those where
R2 and R3 are independently selected from H, (C1-C4)alkyl, halogen or (C1-C4)alkoxy, provided that at least one of R2 and R3 is H.
Other more preferred compounds of Formula I include those where
R1 is amino(C1-C4)alkoxy, mono(C1-C4)alkylamino(C1-C4)alkoxy, di(C1-C4)alkylamino(C1-C4)alkoxy, pyridyl(C1-C4)alkoxy, hydroxy(C1-C4)alkoxy, piperazinyl(C1-C4)alkoxy wherein the piperazinyl group is optionally substituted with (C1-C4)alkyl, or morpholinyl(C1-C6)alkoxy;
R2 and R3 are independently selected from H, (C1-C4)alkyl, or (C1-C4)alkoxy, provided that at least one of R2 and R3 is H.
Within this preferred aspect, other preferred compounds of Formula I are those where both R2 and R3 are both hydrogen.
Yet other preferred compounds of Formula I include those where
R1 is amino(C1-C4)alkoxy, mono(C1-C4)alkylamino(C1-C4)alkoxy, di(C1-C4)alkylamino(C1-C4)alkoxy, pyridyl(C1-C4)alkoxy, hydroxy(C1-C4)alkoxy, piperazinyl(C1-C4)alkoxy wherein the piperazinyl group is optionally substituted with (C1-C4)alkyl, or morpholinyl(C1-C4)alkoxy;
R2 and R3 are independently selected from H, and (C1-C4)alkyl, provided that at least one of R2 and R3 is H.
Within this preferred aspect, other preferred compounds of Formula I are those where both R2 and R3 are both hydrogen.
Even other preferred compounds of Formula I include those where
R1 is amino(C2-C4)alkoxy, mono(C1-C4)alkylamino(C2-C4)alkoxy, di(C1-C4)alkylamino(C2-C4)alkoxy, pyridyl(C2-C4)alkoxy, hydroxy(C2-C4)alkoxy, piperazinyl(C2-C4)alkoxy wherein the piperazinyl group is optionally substituted with (C1-C4)alkyl, or morpholinyl(C2-C4)alkoxy;
R2 is H or methyl; and
R3 is H.
Within this preferred aspect, other preferred compounds of Formula I are those where both R2 and R3 are both hydrogen.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds set forth in Examples 1, 2, and 3 and their pharmaceutically acceptable acid and base addition salts. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-ACOOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The invention also includes hydrates of compounds of Formula I.
The invention includes all crystalline forms of the compounds of Formula I. Certain crystalline forms may be preferred.
The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I. The invention further encompasses all enantiomers and diastereomers of the disclosed compounds. Those of ordinary skill in the art will readily recognize methods by which mixtures of enantiomers and diasteromers may be resolved. The definition of Formula I as used in herein include possible isomers, such as tautomers and rotamers.
This invention relates to 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid amides, preferred examples of which bind with high affinity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Preferred 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid amides, that bind with high selectivity to the benzodiazepine site of GABAA receptors, including human GABAA receptors, are also included in this invention. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of Formula I with the benzodiazepine site results in the pharmaceutical utility of these compounds.
The invention further comprises methods of treating patients in need of such treatment with an amount of a compound of the invention sufficient to alter the symptoms of a CNS disorder. Compounds of the inventions that act as agonists at xcex12xcex23xcex32 and xcex13xe2x8ax963xcex32 receptor subtypes are useful in treating anxiety disorders such as panic disorder, obsessive compulsive disorder and generalized anxiety disorder; stress disorders including post-traumatic stress, and acute stress disorders. Compounds of the inventions that act as agonists at xcex12xcex23xcex32 and xcex13xcex23xcex22 receptor subtypes are also useful in treating depressive or bipolar disorders and in treating sleep disorders. Compounds of the invention that act as inverse agonists at the xcex15xcex23xcex32 receptor subtype or xcex11xcex22xcex32 and xcex15xcex23xcex32 receptor subtypes are useful in treating cognitive disorders including those resulting from Down Syndrome, neurodegenerative diseases such as Alzheimer""s disease and Parkinson""s disease, and stroke related dementia. Compounds of the invention that act as inverse agonists at the xcex15xcex23xcex32 are particularly useful in treating cognitive disorders through the enhancement of memory, and particularly short-term memory, in memory-impaired patients. Compounds of the invention that act as agonists at the xcex11xcex22xcex32 receptor subtype are useful in treating convulsive disorders such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effect of benzodiazepine overdose and in treating drug and alcohol addiction.
The diseases and/or disorders that can also be treated using compounds and compositions according to the invention include:
Depression, e.g. depression, atypical depression, bipolar disorder, depressed phase of bipolar disorder.
Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panic disorder +/xe2x88x92 agoraphobia, social phobia, specific phobia, Post traumatic stress disorder, obsessive compulsive disorder (OCD), dysthymia, adjustment disorders with disturbance of mood and anxiety, separation anxiety disorder, anticipatory anxiety acute stress disorder, adjustment disorders, cyclothymia.
Sleep disorders, e.g. sleep disorders including primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression and/or anxiety or other mental disorders, substance induced sleep disorder.
Cognition Impairment, e.g. cognition impairment, memory impairment, short-term memory impairment, Alzheimer""s disease, Parkinson""s disease, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety or psychosis.
Attention Deficit Disorder, e.g. attention deficit disorder (ADD), and attention deficit and hyperactivity disorder (ADHD). Speech disorders, e.g. stuttering, including motor tic, clonic stuttering, dysfluency, speech blockage, dysarthria, Tourete syndrome or logospasm.
The invention also provides pharmaceutical compositions comprising one or more compounds of the invention together with a pharmaceutically acceptable carrier or excipient, for treating disorders responsive to GABAA receptor modulation, e.g., treatment of anxiety, depression, sleep disorders or cognitive impairment by GABAA receptor modulation. Pharmaceutical compositions include packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of at least one GABAA receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABAA receptor ligand is to be used for treating a disorder responsive to GABAA receptor modulation in the patient.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF1) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer""s dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.
Combination administration can be carried out in a fashion analogous to that disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABAA receptor ligand 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a]phthalzine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABAA receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.
The present invention also pertains to methods of inhibiting the binding of benzodiazepine compounds, such as Ro15-1788, or GABA to the GABAA receptors which methods involve contacting a solution containing compound of the invention with cells expressing GABAA receptors, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine binding or GABA binding to GABAA receptors in vitro. This method includes inhibiting the binding of benzodiazepine compounds to GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to inhibit the binding of benzodiazepine compounds or GABA to GABAA receptors in vitro. In one embodiment, such methods are useful in treating benzodiazepine drug overdose. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine compound to the GABAA receptor may be readily determined via a GABAA receptor binding assay, such as the assay described in Example 6. The GABAA receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABAA receptors.
The present invention also pertains to methods for altering the signal-transducing activity, particularly the chloride ion conductance of GABAA receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to alter the signal-transducing activity of GABAA receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of GABAA receptors may be determined via a GABAA receptor signal transduction assay, such as the assay described in Example 7. The cells expressing the GABA receptors in vivo may be, but are not limited to, neuronal cells or brain cells. Such cells may be contacted with compounds of the invention through contact with a body fluid containing the compound, for example through contact with cerebrospinal fluid. Alteration of the signal-transducing activity of GABAA receptors in vitro may be determined from a detectable change in the electrophysiology of cells expressing GABAA receptors, when such cells are contacted with a compound of the invention in the presence of GABA.
Intracellular recording or patch-clamp recording may be used to quantitate changes in electrophysiology of cells. A reproducible change in behavior of an animal given a compound of the invention may also be used to indicate that changes in the electrophysiology of the animal""s cells expressing GABAA receptors has occurred.
The GABAA receptor ligands provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the GABAA receptor. Radiolabeled derivatives the GABAA receptor ligands provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
More particularly compounds of the invention may be used for demonstrating the presence of GABAA receptors in cell or tissue) samples. This may be done by preparing a plurality of matched cell or tissue samples, at least one of which is prepared as an experiment sample and at least one of which is prepared as a control sample. The experimental sample is prepared by contacting (under conditions that permit binding of RO15-1788 to GABAA receptors within cell and tissue samples) at least one of the matched cell or tissue samples that has not previously been contacted with any compound or salt of the invention with an experimental solution comprising the detectably-labeled preparation of the selected compound or salt at the first measured molar concentration. The control sample is prepared by in the same manner as the experimental sample and also contains an unlabelled preparation of the same compound or salt of the invention at a greater molar concentration.
The experimental and control samples are then washed to remove unbound detectably-labeled compound. The amount of remaining bound detectably-labeled compound is then measured and the amount of detectably-labeled compound in the experimental and control samples is compared. A comparison that indicates the detection of a greater amount of detectable label in the at least one washed experimental sample than is detected in any of control samples demonstrates the presence of GABAA receptors in that experimental sample.
The detectably-labeled compound used in this procedure may be labeled with a radioactive label or a directly or indirectly luminescent label. When tissue sections are used in this procedure and the detectably-labeled compound is radiolabeled, the bound, labeled compound may be detected autoradiographically to generate an autoradiogram. The amount of detectable label in an experimental or control sample may be measured by viewing the autoradiograms and comparing the exposure density of the autoradiograms.
The compounds herein described may have one or more asymmetric centers or planes. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms (racemates), by asymmetric synthesis, or by synthesis from optically active starting materials. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral (enantiomeric and diastereomeric), and racemic forms, as well as all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 3 R*, (where R* indicates any variable group such as Ar, R1, R2, R3 etc.) then said group may optionally be substituted with up to three R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
A dash xe2x80x9cxe2x88x92xe2x80x9d that is not between two letters or symbols is used to indicate a point of attachement for a substituent. For example xe2x80x9cxe2x80x94NHxe2x80x94R60xe2x80x94Yxe2x80x9d is attached through the nitrogen atom.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain aliphatic hydrocarbon groups, having the specified number of carbon atoms. Alkyl groups of 2 or more carbon atoms may contain double or triple bonds. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. Preferred alkyl groups are C1-C6 alkyl groups. xe2x80x9cC1-C6 alkylxe2x80x9d indicates alkyl groups having from 1 to about 6 carbon atoms. More preferred alkyl groups are methyl, ethyl and propyl groups.
As used herein, xe2x80x9calkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. xe2x80x9cC1-C6 alkoxyxe2x80x9d indicates alkoxy groups having from 1 to about 6 carbon atoms. Preferred alkoxy groups are methoxy, ethoxy, propoxy, and botoxy groups.
xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. Alkenyl groups typically have 2 to about 12 carbon atoms, more typically 2 to about 8 carbon atoms and preferably 2-6 carbon atoms.
xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. Alkynyl groups typically have 2 to about 12 carbon atoms, more typically 2 to about 8 carbon atoms and preferably 2-6 carbon atoms.
xe2x80x9cArylxe2x80x9d refers to aromatic groups having 1 or more rings, wherein the members of the aromatic ring or rings are carbon. When indicated such groups may be substituted. Such groups include optionally substituted phenyl and optionally substituted naphthyl.
The term xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cycloalkyl groups typically will have 3 to about 8 ring members.
In the terms xe2x80x9c(cycloalkyl)alkylxe2x80x9d and xe2x80x9calkylxe2x80x9d, defined above, the point of attachment is through a carbon atom in the alkyl group. This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclohexylmethyl. In the term xe2x80x9ccycloalkylxe2x80x9d, the point of attachment is through a ring carbon atom.
As used herein, xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1). Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
As used herein, xe2x80x9chaloalkoxyxe2x80x9d indicates a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy and trichloromethoxy.
As used herein the term xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heteroaryl groups include, but are not limited to, pyrimidinyl, pyridyl, quinolinyl, benzothienyl, indolyl, pryidazinyl, pyazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thienyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl, dihydro-benzodioxinyl, furanyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanonyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide.
Preferred heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and imidazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term xe2x80x9coxoxe2x80x9d indicates the oxygen atom forming carbonyl group. When an oxo group appears as a substituent the allowed valence of the substituted position is not exceeded. When an aryl or heteroaryl group is substituted with oxo the aryl or heteroaryl group is converted to a partially saturated system. For example a pyridyl group substituted with oxo is a pyridone.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOCxe2x80x94(CH2)nxe2x80x94COOH where n is 0-4, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).
The terms xe2x80x9ctrihaloalkylxe2x80x9d and xe2x80x9ctrihaloalkoxyxe2x80x9d refer to particular types of haloalkyl and haloalkoxy groups that contain three halogen atoms, e.g., trichloromethyl, trifluormethyl, and trifluoromethoxy.
The compounds of general Formulas I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formulas I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formulas I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It will be convenient to formulate these animal feed and drinking water compositions so that the animal takes in an appropriate quantity of the composition along with its diet. It will also be convenient to present the composition as a premix for addition to the feed or drinking water.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety, depression, or cognitive impairment a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to high solubility (preferably 500 ng/ml or more) in aqueous solutions, oral bioavailability, low toxicity, low serum protein binding, lack of clinically relevant EKG effects, and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat periphereal disorders are often preferred.
Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcovxc3xa1, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).
Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).